Nonredundancy of IL-1 alpha and IL-1 beta is defined by distinct regulation of tissues orchestrating resistance versus tolerance to infection

Interleukin-1 alpha (IL-1 alpha) and IL-1 beta are inflammatory cytokines with important roles in health and disease. They trigger the same receptor and elicit comparable cellular responses but, for poorly understood reasons, are not redundant in vivo. Here, we decoupled IL-1 alpha and IL-1 beta functions that drive protective responses against invasive infection with group A Streptococcus. IL-1 beta was essential for pathogen clearance, hence resistance to infection, by inducing granulocyte colony-stimulating factor at the infection site and establishing emergency granulopoiesis. In contrast, IL-1 alpha governed reprogramming of liver metabolic pathways associated with tolerance to infection. The IL-1 alpha-dominated hepatic regulation corresponded to high IL-1 alpha levels in the liver during infection. Conversely, IL-1 beta was critical for the regulation of the spleen transcriptome, which correlated with ample IL-1 beta expression in this tissue. The results identify distinct and organ-specific roles of IL-1 alpha versus IL-1 beta and implicate spatial restriction of their expression and bioavailability during infection as the underlying mechanism.